This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Cardiovascular Disease (CVD) and related disorders remain the leading cause of death in the nation . Hypovitaminosis D has been linked not only to several cardiovascular (CV) risk factors including hypertension, diabetes, obesity , , but also to increased rates of CVD. Thus, hypovitaminosis D presents a common pathway for a select subgroup with a clustering of CV risk factors in a profile that is predominant among ethnic minorities. Indeed, hypovitaminosis D is highly prevalent with an estimated 55% of the US adult population having levels at or below 30 ng/ml, and over 80% of African Americans having suboptimal values. A large body of evidence supports the premise that therapeutic agents that have salutary effects on vascular function, often translate into therapeutic benefits on 'harder'clinical endpoints such as adverse CV events and mortality. Exploring the potential vascular effects of vitamin D repletion presents a unique opportunity to examine both clinical outcomes and specific mechanistic pathways of a potentially modifiable intervention that could result in significant impact at a public health level. Thus, we propose a twelve week randomized double-blind, placebo controlled pilot trial to assess the effect on vascular function and CV risk factors of 100,000 IU Vitamin D3 given every 4 weeks to overweight, hypertensive African-Americans with hypovitaminosis D. To our knowledge, the proposed project is the first to assess the effect of 'high-dose'Vitamin D3 administration on vascular function. We believe this study is also the first to examine the impact at a molecular level of Vitamin D3 repletion on the key mediators of cardio-metabolic pathways in humans. If our study results support our working hypothesis, we will be positioned to propose a larger scale study to detect a therapeutic effect on more definitive, clinical cardiovascular endpoints across a more diverse population. Hypothesis: Hypovitaminosis D activates select vasconstrictive and hypertrophic mediators that lead to endothelial dysfunction, elevated blood pressure and CVD;and Vitamin D3 repletion (using evidenced-based repletion strategies), in comparison to placebo, will ameliorate these abnormalities.
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